Drug abusers vary widely in their acute and chronic responses to drugs and in their response to drug abuse treatment. A better understanding of the factors associated with individual differences in response should result in the development of more effective and efficient diagnostic and treatment approaches. This project assesses biological and psychosocial characteristics of drug abusers and correlates them with abusers'response to their abused drug, their biomedical consequences from drug use (such as HIV infection), or to the abusers'treatment outcome. One component is evaluating the psychological, physiological, and neuropharmacological manifestations and time course of cocaine withdrawal, with the goal of identifying predictors of relapse to cocaine use. This study, in collaboration with the Department of Radiology, Johns Hopkins University, uses positron emission tomography (PET) scanning with 11C-carfentanil (a synthetic, potent mu-opiate receptor agonist) to evaluate the effect of chronic cocaine abuse on mu-opiate receptor function in the brain. Electroencephalogram (EEG) and cerebral artery blood flow (by transcranial Doppler) are evaluated in collaboration with the Molecular Neuropsychiatry Branch. Results indicate that chronic heavy cocaine users have increased mu-opiate receptor binding in some brain regions (compared to non-drug using healthy controls). The increased binding persists in some brain regions over 12 weeks of cocaine abstinence, as does the increased pulsatility of cerebral arteries. Psychological (e.g., cocaine craving, mood) and other physiological parameters (sleep, heart rate) normalize over 7-10 days. Changes in receptor binding are associated with cocaine craving and tendency to relapse during outpatient treatment for cocaine dependence. These findings suggest an important role for the brain mu-opiate system in cocaine addiction, with interesting treatment implications. The current phase of the cocaine withdrawal project, in collaboration with the Treatment Section, is evaluating the relationship between brain mu-opiate receptor function (assessed by PET scanning) and response to outpatient treatment and cognitive function (especially risk-reward decision-making) among cocaine addicts. The project has expanded to include study of marijuana withdrawal, in collaboration with the Maryland Psychiatric Research Center. Initial findings are that marijuana users who attempt to stop use without professional treatment experience a withdrawal syndrome with primarily psychological symptoms, may relapse to marijuana use to self-medicate withdrawal symptoms, and use coping strategies similar to those used by those quitting alcohol or tobacco use. These findings suggest that marijuana withdrawal can serve as a negative reinforcer for relapse and, therefore, could be a fruitful focus of treatment for marijuana abuse. Current studies are evaluating this issue in larger samples and in subjects with psychiatric comorbidities such as schizophrenia, attention deficit disorder, and other drug abuse. A second component of this project assesses psychiatric and medical co-morbidity (including HIV infection), personality traits, mood, neuropsychological function, and sociodemographic characteristics in drug abusers and other clinically relevant populations (e.g., trauma inpatients) using structured and semi-structured diagnostic interviews and computer-administered psychological tests. A third component evaluates the subclinical effects of acute and chronic cocaine use on cardiovascular function, using 24-hour ambulatory monitoring, high-resolution EKG, echocardiography, and analysis of heart rate variability. A fourth component is evaluating individual differences in activity of the main cocaine-metabolizing enzyme in humans, butyrylcholinesterase, and of various neurotransmitter-associated genotypes (in collaboration with the Molecular Neurobiology Branch) as factors influencing the acute response to cocaine.